US11180504B2 - Substituted carbapenems for the treatment of bacterial infections - Google Patents

Substituted carbapenems for the treatment of bacterial infections Download PDF

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US11180504B2
US11180504B2 US16/083,980 US201716083980A US11180504B2 US 11180504 B2 US11180504 B2 US 11180504B2 US 201716083980 A US201716083980 A US 201716083980A US 11180504 B2 US11180504 B2 US 11180504B2
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US20200291029A1 (en
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Gopalan Balasubramanian
Maneesh Paul-Satyaseela
Chidambaram Venkateswaran Srinivasan
Sridhar Ramanathan Iyer
Hariharan Periasamy
Venkatesan Parameswaran
Bharani Thirunavukkarasu
Prabhakar Rao Gunturu
Manjula Devi Deshkumar
Venkateshwarlu Jakkala
Michael Miller
Ravi P. Nargund
Sheo Singh
Shuzhi Dong
Hongwu Wang
Katherine Young
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Orchid Pharma Ltd
Merck Sharp and Dohme LLC
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Orchid Pharma Ltd
Merck Sharp and Dohme LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • carbapenem compounds Described herein are carbapenem compounds, their stereoisomers, pharmaceutically acceptable salts or V-oxides thereof, which may be useful for the treatment of bacterial infections, particularly drug-resistant bacterial infections. Also described herein are the processes for the preparation of compounds, the pharmaceutical compositions of these compounds and their use in the treatment of bacterial infection.
  • Antimicrobial resistance is the most important crisis in the antibacterial therapy.
  • One of the mechanisms of resistance development is due to enzymes, which deactivate certain class of antibiotics by hydrolysis, e.g. ⁇ -lactam ring of ⁇ -lactam antibiotics.
  • the enzymes which are responsible for the deactivation of the ⁇ -lactams are ⁇ -lactamases, particularly Extended Spectrum ⁇ -Lactamase (ESBL).
  • ESBL Extended Spectrum ⁇ -Lactamase
  • ESBL is produced mainly by Enterobacteriaceae group (Chaudhary et al., Indian Journal of Medical Microbiology, 2004, 22(2), 75-80, Extended Spectrum ⁇ -Lactamases (ESBL)—An Emerging Threat to Clinical Therapeutics).
  • the risk factors involved in the expression of ESBL are increased length of hospitalization or ICU stay, increased severity of illness, use of a central venous or arterial catheter or urinary catheter, ventilatory support, hemodialysis, emergency abdominal surgery, gastrostomy or jejunostomy, gut colonization, prior administration of antibiotics, particularly of oxyimino- ⁇ -lactams (Falagas et al., Journal of Antimicrobial Chemotherapy, 2007, 60, 1124-1130, Risk factors of carbapenem-resistant Klebsiella pneumoniae infections: a matched case—control study).
  • Carbapenems such as Imipenem (U.S. Pat. No. 4,194,047 A), Meropenem (European Pat. No. EP0126587 B1), Ertapenem (European Pat. No. EP0579826 B1) and Doripenem (European Pat. No. EP0528678 B1) are ultrabroad spectrum injectable antibiotics. These antibiotics give rise to cell death by binding to penicillin-binding proteins (PBPs) and inhibiting cell wall biosynthesis. The emergence of carbapenemases belonging to class A and class D ⁇ -lactamases threatens their clinical utility.
  • PBPs penicillin-binding proteins
  • Carbapenem compounds with potency against carbapenem-resistant gram negative bacteria have not been reported. Therefore, the development of a novel carbapenem compound with broad antibacterial spectrum, preferably a compound possessing potent activity against resistant bacteria which produce ⁇ -lactamase is desirable.
  • the objective of the present invention is to provide carbapenem compounds, their stereoisomers, pharmaceutically acceptable salts or N-oxides thereof.
  • Yet another objective of the present invention is to provide processes for the preparation of Carbapenem compounds and pharmaceutical compositions containing these compounds.
  • a further objective of the present invention is to provide a method for preventing or treating bacterial infection and to provide carbapenem compounds as broad spectrum antibacterial agents.
  • the present invention relates to novel carbapenems.
  • the present invention relates to a compound of formula ((I), (Ia) or (Ib), or a stereoisomer, internal salt, N-oxide, or pharmaceutically acceptable salt thereof.
  • the compounds of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt, N-oxide, or pharmaceutically acceptable salt thereof can be useful in the treatment of bacterial infections.
  • the present invention relates to compounds of formula (I)
  • A represents —NR 0 R or —OR z ;
  • Z represents —H or —CH 3 ;
  • X represents —S— or —CH 2 —
  • R z represents isoxazolyl
  • R 0 is hydrogen or C 1-6 alkyl which is optionally substituted with one or two substituents selected from halogen, hydroxyl, cyano, carbamoyl, —SO 2 NH 2 and C 1-6 alkoxy;
  • R is:
  • R and R 0 together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • n is an integer selected from 0, 1, 2, 3, 4, 5 and 6;
  • R 1 is:
  • R 2 is:
  • R 4 is —COO ⁇ or —COOR 5 ;
  • R 5 is hydrogen, a carboxylic acid protecting group or an ester prodrug moiety
  • AryA is 1) a substituted or unsubstituted 5- or 6-membered aromatic ring with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, or
  • HetA is a substituted or unsubstituted 5- to 10-membered saturated ring with 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, wherein any S atom in the ring is optionally oxidized;
  • AryC is 1) a substituted or unsubstituted 5- or 6-membered aromatic ring with 0, 1, 2 or 3 heteroatom ring atoms independently selected from N, O and S, wherein the N atom is optionally quaternized with —CH 3 , or
  • HetC is a substituted or unsubstituted 4- to 8-membered saturated ring with 1 or 2 heteroatom ring atoms selected from N, O or S;
  • R a is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, —CR x ( ⁇ NR x ), —C( ⁇ NR x )N(R x ) 2 , —CH 2 C( ⁇ O)N(R x ) 2 , —(CH 2 ) 1-6 OR x or —SO 2 C 1-6 alkyl;
  • R b is hydrogen or C 1-3 alkyl
  • R d is hydrogen, C 1-3 alkyl, C 1-3 hydroxyalkyl or C 1-3 cyanoalkyl, or
  • R c and R d are taken together, with the N to which they are attached, to form a substituted or unsubstituted 4- to 12-membered heterocyclic ring or ring system with 0, 1, or 2 additional heteroatom ring atoms independently selected from N, O, and S, wherein the rings in the heterocyclic ring system can be bridged, fused, spiro-linked or any combination of two thereof; wherein any nitrogen ring atom of the heterocyclic ring or ring system is optionally quadricovalent; and wherein the heterocyclic ring or ring system is optionally substituted with 1, 2, 3 or 4 substituents independently selected from
  • R f is H, —C( ⁇ O)N(C 1-6 alkyl) 2 , —SO 2 C 1-6 alkyl, —SO 2 N(R x ) 2 , —C( ⁇ O)-cyclopentyl-N(R x ) 2 , —C( ⁇ O)-pyridinyl optionally substituted with one or more groups selected from oxo, —C 1-3 alkyl and —OH, —C( ⁇ O)-pyrrolidinyl substituted with —NR a R b or halogen, —C( ⁇ O)-thiazolidinyl, —SO 2 -piperazine, or —SO 2 -pyrrolidinyl-N(R x ) 2 ;
  • R g is hydrogen or C 1-3 alkyl, or
  • R f and R g are taken together, with the N to which they are attached, to form morpholinyl; piperazinyl; pyrrolidinyl optionally substituted with —CH 3 ; piperidinyl or thiomorpholinyl optionally substituted with —C 1-6 alkyl or —N(R x ) 2 ; or triazolyl substituted with —CH 2 NH 2 ;
  • R h and R j is independently H, C 1-6 alkyl, or C 3-8 cycloalkyl;
  • R i is —C 1-5 amino alkyl, —OC 1-6 alkyl, —C 1-3 cyanoalkyl, or —C 1-6 haloalkyl optionally substituted with —NR x R y ;
  • R k is C 1-6 alkyl, or thiazole substituted with —NH 2 ;
  • each R x and R y is independently hydrogen or C 1-3 alkyl
  • the present invention also relates to compounds of formula (Ib)
  • A represents —NR 0 R or —OR z ;
  • R z represents isoxazolyl
  • R 0 is hydrogen or C 1-6 alkyl which is optionally substituted with one or two substituents selected from halogen, hydroxyl, cyano, carbamoyl, —SO 2 NH 2 and C 1-6 alkoxy;
  • R is:
  • R and R 0 together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • n is an integer selected from 0, 1, 2, 3, 4, 5 and 6;
  • R 1 is:
  • R 2 is:
  • R 4 is —COO ⁇ or —COOR 5 ;
  • R 5 is hydrogen, a carboxylic acid protecting group or an ester prodrug moiety
  • Ary A is 1) a substituted or unsubstituted 5- or 6-membered aromatic ring with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, or
  • HetA is a substituted or unsubstituted 5- to 10-membered saturated ring with 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, wherein any S atom in the ring is optionally oxidized;
  • AryC is 1) a substituted or unsubstituted 5- or 6-membered aromatic ring with 1, 2 or 3 heteroatom ring atoms independently selected from N, O and S, or
  • HetC is a substituted or unsubstituted 4- to 6-membered saturated ring with 1 or 2 heteroatom ring atoms selected from N, O or S;
  • R a is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, —CR x ( ⁇ NR x ), —C( ⁇ NR x )N(R x ) 2 , —CH 2 C( ⁇ O)N(R x ) 2 , or —SO 2 C 1-6 alkyl;
  • R b is hydrogen or C 1-3 alkyl
  • R c is H; —C 1-6 alkyl optionally substituted with —NR h R j , —CN or —OH;
  • —(CH 2 ) 1-3 -pyridinyl optionally substituted with one or more groups selected from —CH 3 , —OH, and oxo; or
  • R d is hydrogen, C 1-3 alkyl, C 1-3 hydroxyalkyl or C 1-3 cyanoalkyl; or
  • R c and R d are taken together, with the N to which they are attached, to form a substituted or unsubstituted 4- to 12-membered heterocyclic ring or ring system with 0, 1, or 2 additional heteroatom ring atoms independently selected from N, O, and S, wherein the rings in the heterocyclic ring system can be bridged, fused, spiro-linked or any combination of two thereof; wherein any nitrogen ring atom of the heterocyclic ring or ring system is optionally quadricovalent; and wherein the heterocyclic ring or ring system is optionally substituted with 1, 2, 3 or 4 substituents independently selected from
  • R f is H; —C( ⁇ O)N(C 1-6 alkyl) 2 ; —SO 2 C 1-6 alkyl; —SO 2 N(R x ) 2 ; —C( ⁇ O)-cyclopentyl-N(R x ) 2 ; —C( ⁇ O)-pyridinyl optionally substituted with one or more groups selected from oxo, —C 1-3 alkyl and —OH; —C( ⁇ O)-pyrrolidinyl substituted with —NR a R b or halogen; —C( ⁇ O)-thiazolidinyl; —SO 2 -piperazine; or —SO 2 -pyrrolidinyl-N(R x ) 2 ;
  • R g is hydrogen or C 1-3 alkyl
  • R f and R g are taken together, with the N to which they are attached, to form morpholinyl; piperazinyl; pyrrolidinyl optionally substituted with —CH 3 ; piperidinyl or thiomorpholinyl optionally substituted with —C 1-6 alkyl or —N(R x ) 2 ; or triazolyl substituted with —CH 2 NH 2 ;
  • R h and R j is independently H, C 1-6 alkyl, or C 3-8 cycloalkyl;
  • R i is —C 1-5 amino alkyl; —OC 1-6 alkyl; —C 1-3 cyanoalkyl; or —C 1-6 haloalkyl optionally substituted with —NR x R y ;
  • R k is C 1-6 alkyl; or thiazole substituted with —NH 2 ;
  • each R x and R y is independently hydrogen or C 1-3 alkyl
  • the present invention also relates to a compound of formula (Ia), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • described herein is also a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), (Ia) or (Ib), or a stereoisomer, pharmaceutically acceptable salt or N-oxide thereof.
  • the compounds described herein can also be combined with appropriate ⁇ -lactamase inhibitors to increase the antibiotic spectrum. In another aspect, the compounds described herein can also be combined with appropriate dehydropeptidase inhibitors.
  • described herein is a process for preparation of a compound of formula (I), (Ia) or (Ib), or a stereoisomer, pharmaceutically acceptable salt or N-oxide thereof.
  • described herein is also a method for preventing or treating a bacterial infection comprising administering a therapeutically effective amount of a compound of formula (I), (Ia) or (Ib), or a stereoisomer, pharmaceutically acceptable salt, pharmaceutical composition or N-oxide thereof.
  • described herein is also a method for preventing or treating a gram negative and/or gram positive bacterial infection comprising administering a therapeutically effective amount of a compound of formula (I), (Ia) or (Ib), or a stereoisomer, pharmaceutically acceptable salt, pharmaceutical composition or N-oxide thereof.
  • described herein is also a method for preventing or treating a bacterial infection comprising administering a therapeutically effective amount of a compound of formula (I), (Ia) or (Ib), in combination or alternation with one or more other antimicrobial agents.
  • the present invention is based, in part, on the discovery of carbapenem derivatives that are bacteriocidal against a broad spectrum of bacteria.
  • the present invention relates to compound of formula (I), (Ia) or (Ib), as described above, or a stereoisomer, internal salt, N-oxide, or pharmaceutically acceptable salt thereof.
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein A represents —NR 0 R, and the other groups are as provided in the general formula for formula (I), (Ia) or (Ib).
  • A represents —NR 0 R.
  • X is —S—.
  • Z is —CH 3 .
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • R 0 is hydrogen or methyl
  • R 0 is hydrogen or methyl
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1, and the other groups are as provided in the general formula for formula (I), (Ia) or (Ib), above or in the embodiments. In one aspect of this embodiment, n is 0.
  • n is 0 or 1. In one aspect of this embodiment, n is 0.
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R 1 is: —(CH 2 ) 0-2 -AryC or —(CH 2 ) 0-1 -HetC, and the other groups are as provided in the general formula for formula (I), (Ia) or (Ib), above or any of the embodiments.
  • R 1 is —(CH 2 ) 0-2 -AryC or —(CH 2 ) 0-1 -HetC.
  • R 4 is —COOH
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt, N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • Ary A is 1) a 5- to 6-membered aromatic ring with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, —(CH 2 ) 0-1 NR x R y , C 3 -C 8 cycloalkyl, —COOH, —COOC 1-6 alkyl, C 1-6 alkoxy, thienyl, and tetrazolyl, or
  • HetA is a 5- to 10-membered saturated ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, —NR x R y , —CH 2 NR x R y , —OH, and oxo;
  • AryC is 1) a 5- or 6-membered aromatic ring with 0, 1 or 2 heteroatom ring atoms independently selected from N and S, optionally quaternized with CH 3 and optionally substituted 1 to 3 substituents independently selected from —CH 2 NR x R y , —CH 2 -pyrrolidinyl, —OH, oxo, pyridinyl which is optionally quaternized with methyl or —CH 2 CONH 2 , or
  • HetC is a 4- to 8-membered saturated ring with 1 or 2 N or O ring atoms, optionally substituted with 1 or 2 substituents independently selected from halogen, —OH, —C 1-6 alkyl, —(CH 2 ) 0-3 NR f R g , —CH ⁇ NH, —C( ⁇ O)C 1-6 alkyl, —C( ⁇ NH) —NH 2 , —CH 2 —(C ⁇ O)-pyrrolidinyl optionally substituted with —NR x R y , —NH—C( ⁇ NH) —NH 2 , —CH 2 —NH—C( ⁇ NH) —NH 2 , —C( ⁇ O)C 1-6 aminoalkyl, —C( ⁇ O)NR c R d , —NR x R y , —NHSO 2 NR x R y , —SO 2 NR c R d , thiazolyl, and
  • AryA is 1) a 5- to 6-membered aromatic ring with 0, 1, 2, 3 or 4 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, —(CH 2 ) 0-1 NRxRy, C 1 -C 6 cycloalkyl, —COOH, —COOC 1-6 alkyl, C 1-6 alkoxy, thienyl, and tetrazolyl; or
  • HetA is a 5- or 6-membered saturated ring with 1 or 2 heteroatom ring atoms independently selected from N, O and S, optionally substituted with 1 or 2 substituents independently selected from halo, —NR x R y , —OH, and oxo;
  • AryC is 1) a 5- or 6-membered aromatic ring with 1 or 2 heteroatom ring atoms independently selected from N and S, optionally substituted 1 to 3 substituents independently selected from —CH 2 NR x R y , —OH, oxo, pyridinyl which is optionally quaternized with methyl; or
  • HetC is a 4- to 6-membered saturated ring with 1 or 2 N ring atoms, optionally substituted with 1 or 2 substituents independently selected from halo; —C 1-6 alkyl optionally substituted with —NR f R g ; —CH ⁇ NH; —C( ⁇ O)C 1-6 alkyl;
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof,
  • R d is hydrogen, or C 1-3 alkyl
  • R c and R d are taken together, with the N to which they are attached, to form
  • R c is H; —CH 2 CN; —C 1-6 alkyl optionally substituted with —NR h R j or —OH; —CH 2 CH 2 C( ⁇ O)NR x R y ; —CH 2 CH 2 C( ⁇ O)NHCH 2 CH 2 OH;
  • R d is hydrogen or C 1-3 alkyl
  • R c and R d are taken together, with the N to which they are attached, to form
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein:
  • R 0 is hydrogen and R is:
  • R 0 is hydrogen and R is:
  • R 0 is hydrogen or C 1-6 alkyl which is optionally substituted with one or two substituents selected from halogen, hydroxyl, cyano, carbamoyl, —SO 2 NH 2 and C 1-6 alkoxy;
  • R is:
  • R and R 0 together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S.
  • R 0 is hydrogen or C 1-6 alkyl which is optionally substituted with one or two substituents selected from halogen, hydroxyl, cyano, carbamoyl, —SO 2 NH 2 and C 1-6 alkoxy;
  • R is:
  • R and R 0 together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S.
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R 0 is hydrogen and R is:
  • R and R 0 combine together to form -triazolyl optionally substituted with —CH 2 —OH; and the other groups are as provided in the general formula for formula (I), (Ia) or (Ib), above.
  • R 0 is hydrogen and R is:
  • R and R 0 combine together to form -triazolyl optionally substituted with —CH 2 —OH.
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R 1 is:
  • R 1 is:
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R 1 is pyrrolidinyl substituted with
  • R 1 is pyrrolidinyl substituted with
  • the present invention relates to a compound of formula (Ia), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof,
  • the compound has a structure according to formula Ia:
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • R 0 is hydrogen or C 1-6 alkyl which is optionally substituted with one or two substituents selected from halogen, hydroxyl, cyano, carbamoyl, —SO 2 NH 2 and C 1-6 alkoxy;
  • R is:
  • R and R 0 together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S, provided that when R and R 0 together with the N to which they are attached form triazole, then Z is not H.
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof,
  • R 0 is hydrogen or C 1-6 alkyl which is optionally substituted with one or two substituents selected from halogen, hydroxyl, cyano, carbamoyl, —SO 2 NH 2 and C 1-6 alkoxy;
  • R is:
  • R and R 0 together with the N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S, provided that when R and R 0 together with the N to which they are attached form triazole or tetrazole, then Z is not H.
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • R is —(CH 2 ) n C( ⁇ O)R 2 , —(CH 2 ) n C( ⁇ S)R 2 , —(CH 2 ) n SO 2 R 2 , or —CH( ⁇ NH); or
  • R and R 0 together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • R is —(CH 2 ) n C( ⁇ O)R 2 , n is 0 and R 0 is H, then R 2 is not unsubstituted C 1-6 alkyl;
  • R is —(CH 2 ) n C( ⁇ O)R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • R is —(CH 2 ) n SO 2 R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • R is —(CH 2 ) n C( ⁇ O)R 2 , —(CH 2 ) n C( ⁇ S)R 2 , —(CH 2 ) n SO 2 R 2 , or —CH( ⁇ NH); or
  • R and R 0 together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • R is —(CH 2 ) n C( ⁇ O)R 2 , n is 0 and R 0 is H, then R 2 is not unsubstituted C 1-6 alkyl;
  • R is —(CH 2 ) n C( ⁇ O)R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • R is —(CH 2 ) n SO 2 R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • R is —(CH 2 ) n C( ⁇ O)R 2 , —(CH 2 ) n C( ⁇ S)R 2 , —(CH 2 ) n SO 2 R 2 , or —CH( ⁇ NH); or
  • R and R 0 together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • R 2 is not unsubstituted C 1-6 alkyl
  • R is —(CH 2 ) n C( ⁇ O)R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • R is —(CH 2 ) n SO 2 R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R is —(CH 2 ) n C( ⁇ O)R 2 , —(CH 2 ) n C( ⁇ S)R 2 , —(CH 2 ) n SO 2 R 2 , or —CH( ⁇ NH); or
  • R and R 0 together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • R is —(CH 2 ) n C( ⁇ O)R 2 , n is 0 and R 0 is H, then R 2 is not unsubstituted C 1-6 alkyl;
  • R is —(CH 2 ) n C( ⁇ O)R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • R 2 is —(CH 2 ) n SO 2 R 2 and n is not 0, R 2 is not OH;
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R is —(CH 2 ) n C( ⁇ O)R 2 , —(CH 2 ) n C( ⁇ S)R 2 , —(CH 2 ) n SO 2 R 2 , or —CH( ⁇ NH); or
  • R and R 0 together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • R is —(CH 2 ) n C( ⁇ O)R 2 , n is 0 and R 0 is H, then R 2 is not unsubstituted C 1-6 alkyl;
  • R is —(CH 2 ) n C( ⁇ O)R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • R 0 is not H;
  • R 2 is —(CH 2 ) n SO 2 R 2 and n is not 0, R 2 is not OH;
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein R is —(CH 2 ) n C( ⁇ O)R 2 , —(CH 2 ) n C( ⁇ S)R 2 , —(CH 2 ) n SO 2 R 2 , or —CH( ⁇ NH); or
  • R and R 0 together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • R is —(CH 2 ) n C( ⁇ O)R 2 , n is 0 and R 0 is H, then R 2 is not unsubstituted C 1-6 alkyl;
  • R is —(CH 2 ) n C( ⁇ O)R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • R 0 is not H;
  • R 2 is —(CH 2 ) n SO 2 R 2 and n is not 0, R 2 is not OH;
  • the present invention relates to a compound of formula (I), (Ia) or (Ib), or a stereoisomer, internal salt N-oxide, or pharmaceutically acceptable salt thereof, wherein
  • R is —(CH 2 ) n C( ⁇ O)R 2 , —(CH 2 ) n C( ⁇ S)R 2 , —(CH 2 ) n SO 2 R 2 , or —CH( ⁇ NH); or
  • R and R 0 together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • R is —(CH 2 ) n C( ⁇ O)R 2 , n is 0 and R 0 is H, then R 2 is not unsubstituted C 1-6 alkyl;
  • R is —(CH 2 ) n C( ⁇ O)R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • R 0 is not H
  • R 2 is not OH.
  • R is —(CH 2 ) n C( ⁇ O)R 2 , —(CH 2 ) n C( ⁇ S)R 2 , —(CH 2 ) n SO 2 R 2 , or —CH( ⁇ NH); or
  • R and R 0 together with N to which they are attached form a substituted or unsubstituted 5-6 membered cyclic ring with 0, 1, 2, 3 or 4 additional heteroatom ring atoms independently selected from N, O and S;
  • R 0 is not H;
  • R is —(CH 2 ) n C( ⁇ O)R 2 and n is not 0, R 2 is not OH or NH 2 ;
  • R 0 is not H
  • R 2 is not OH.
  • R 1 is C 2-6 aminoalkyl optionally substituted with —CR x ⁇ NR x .
  • A represents —NR 0 R. In another embodiment, A represents —OR z .
  • Z represents —H. In another embodiment, Z represents —CH 3 .
  • X represents —S—. In another embodiment, X represents —CH 2 —.
  • R 0 is hydrogen
  • R is —(CH 2 ) n C( ⁇ O)R 2 .
  • R 1 is —(CH 2 ) 0-6 -HetC or —(CH 2 ) 1-6 NH(C ⁇ NH)NH 2 .
  • R 1 is HetC or —(CH 2 ) 2 —NH(C ⁇ NH)NH 2 .
  • R 1 is —(CH 2 ) 0-6 -HetC. In another embodiment, R 1 is -HetC.
  • R 1 is —(CH 2 ) 1-6 NH(C ⁇ NH)NH 2 . In another embodiment, R 1 is —(CH 2 ) 2 —NH(C ⁇ NH)NH 2 .
  • R 2 is AryA. In another embodiment, R 2 is tetrazole.
  • R 4 is —CO 2 H.
  • HetC is a substituted or unsubstituted pyrrolidine.
  • R c is —C( ⁇ NH)-pyrrobdin-1-yl substituted with NH 2 .
  • R d is hydrogen
  • R c and R d are taken together, with the N to which they are attached, to form a a heterocyclic ring or ring system selected from: azetidine, pyrrolidine, piperazine, octahydropyrrolo[3,4-b]pyrrole, octahydro-1H-pyrrolo[3,2-c]pyridine, 2,7-diazaspiro[4,4]-nonane, octahydropyrrolo[3,4-d]imidazole, and 3,8-diaza-tricyclo[5.2.1.01,5]decane, wherein the heterocyclic ring or ring system is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: ⁇ NH, —(CH 2 ) 0-3 OH, —CH 2 CH(OH)CH 2 NH 2 , —(CH 2 ) 0-3 NR h R j optionally substituted with —NH 2 , —NHC(
  • R c and R d are taken together, with the N to which they are attached, to form a a heterocyclic ring or ring system selected from: azetidine, pyrrolidine, piperazine, octahydropyrrolo[3,4-b]pyrrole, octahydro-1H-pyrrolo[3,2-c]pyridine, 2,7-diazaspiro[4,4]-nonane, octahydropyrrolo[3,4-d]imidazole, and 3,8-diaza-tricyclo[5.2.1.01,5]decane, wherein the heterocyclic ring or ring system is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: ⁇ NH, —CH 2 OH, OH, —CH 2 CH(OH)CH 2 NH 2 , —(CH 2 ) 3 NH 2 optionally substituted with —NH 2 , —CH 2 CH(NH 2 )CH 2 NH
  • each R x and R y is independently hydrogen.
  • HetC is substituted with one substituent selected from —C( ⁇ O)NR c R d .
  • the pharmaceutically acceptable salt is selected from sodium, potassium, calcium, magnesium and ammonium salts.
  • the compound of the invention is selected from the exemplary species depicted in EXAMPLES 1 to 601 shown below, and pharmaceutically acceptable salts thereof.
  • the compound of the invention is selected from the exemplary species depicted in EXAMPLES 32, 44, 95, 103, 106, 112, 120, 121, 124, 129, 132, 135, 146, 149, 157, 158, 159, 161, 168, 169, 176, 178, 184, 186, 218, 219, 221, 242,264, 278, 283, 298, 314, 324, 352, 360, 361, 362, 363, 364, 365, 366, 367, 368, 391, 395, 396, 397, 398, 400, 404, 411, 412, 413, 414, 419, 420, 425, 426, 427, 429, 431, 432, 433, 435, 437, 438, 439. 457, 481, 493, 505, 521, 523, 544, 545, 560, 566, 567, 571, 575, 576, 580, 584,
  • the present invention also includes a compound of Formula I or Ia or Ib, or a pharmaceutically acceptable salt thereof,
  • the compounds of the present invention can optionally be employed in combination with one or more beta-lactamase inhibitors.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(i) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub-embodiments, classes or sub-classes described above.
  • the compound may optionally be used in the form of a pharmaceutically acceptable salt in these embodiments.
  • each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (i) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments.
  • Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present invention or its salt employed therein is substantially pure.
  • Alkyl means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, and the like.
  • Alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
  • Antibiotic refers to a compound or composition which decreases the viability of a microorganism, or which inhibits the growth or proliferation of a microorganism.
  • the phrase “inhibits the growth or proliferation” means increasing the generation time (i.e., the time required for the bacterial cell to divide or for the population to double) by at least about 2-fold.
  • Preferred antibiotics are those which can increase the generation time by at least about 10-fold or more (e.g., at least about 100-fold or even indefinitely, as in total cell death).
  • an antibiotic is further intended to include an antimicrobial, bacteriostatic, or bactericidal agent.
  • “About”, when modifying the quantity (e.g., kg, L, or equivalents) of a substance or composition, or the value of a physical property, or the value of a parameter characterizing a process step (e.g., the temperature at which a process step is conducted), or the like refers to variation in the numerical quantity that can occur, for example, through typical measuring, handling and sampling procedures involved in the preparation, characterization and/or use of the substance or composition; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make or use the compositions or carry out the procedures; and the like.
  • “about” can mean a variation of ⁇ 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 of the appropriate unit. In certain embodiments, “about” can mean a variation of ⁇ 1%, 2%, 3%, 4%, 5%, 10%, or 20%.
  • Aromatic ring system as exemplified herein, by Ary A, AryB and AryC, means monocyclic, bicyclic or tricyclic aromatic ring or ring system containing 5-14 ring atoms, wherein at least one of the rings is aromatic.
  • Aromatic ring systems as used herein, encompass aryls and heteroaryls. The term may be used to describe a carbocyclic ring fused to an aryl group.
  • a 5-7-membered cycloalkyl can be fused through two adjacent ring atoms to a 5-6-membered heteroaryl containing 1, 2, or 3 heteroatom ring atoms selected from N, O, and S.
  • a heteromonocyclic ring is fused through two ring atoms to a phenyl or 5-6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.
  • Aryl means a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 6-14 carbon atoms, wherein at least one of the rings is aromatic.
  • aryl include phenyl and naphthyl.
  • Cycloalkyl means a saturated monocyclic, bicyclic or bridged carbocyclic ring, having a specified number of carbon atoms.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Drug resistant means, a bacterium which is no longer susceptible to at least one previously effective drug; which has developed the ability to withstand antibiotic attack by at least one previously effective drug.
  • a drug resistant strain may relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.
  • Halogen includes fluorine, chlorine, and bromine.
  • Heteroaryl means monocyclic, bicyclic or tricyclic ring or ring system containing 5-14 carbon atoms and containing at least one ring heteroatom selected from N, NH, a N as a quaternary salt, S (including SO and SO 2 ) and O, wherein at least one of the heteroatom containing rings is aromatic.
  • heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzothienyl (including S-oxide and dioxide), benzotriazolyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like.
  • Heterocycle means monocyclic, bicyclic or tricyclic saturated or monounsaturated ring or ring system containing 3-14 carbon atoms and containing at least one ring heteroatom selected from N, NH, a N as a quaternary salt, S (including SO and SO 2 ) and O.
  • a heterocycle contains two rings, the rings may be fused, bridged or spiro-linked.
  • monocyclic heterocycle rings include piperazine, piperidine, and morpholine.
  • the rings may be fused, bridged and/or spiro-linked.
  • monocyclic heterocycle rings include piperazine, piperidine, and morpholine.
  • tricyclic ring systems include 8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine
  • Oxo means an oxygen atom connected to another atom by a double bond and is can be represented “ ⁇ O”.
  • Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, as originally defined or as defined in any of the foregoing embodiments, sub-embodiments, aspects, classes or sub-classes, wherein the compound or its salt is in a substantially pure form.
  • substantially pure means suitably at least about 60 wt. %, typically at least about 70 wt. %, preferably at least about 80 wt. %, more preferably at least about 90 wt. % (e.g., from about 90 wt. % to about 99 wt. %), even more preferably at least about 95 wt. % (e.g., from about 95 wt.
  • a product containing a compound of Formula I or its salt e.g., the product isolated from a reaction mixture affording the compound or salt
  • the level of purity of the compounds and salts can be determined using a standard method of analysis such as thin layer chromatography, gel electrophoresis, high performance liquid chromatography, and/or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined, then the method providing the highest level of purity governs.
  • a compound or salt of 100% purity is one which is free of detectable impurities as determined by a standard method of analysis.
  • a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer. All isomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present invention.
  • any variable e.g., R 1 , R a , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a squiggly line across a bond in a substituent variable represents the point of attachment.
  • substituted shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.
  • substitutions can also be occur where such group is part of a larger substituent, e.g., —C 1-8 alkyl-C 3-7 cycloalkyl and —C 1-8 alkyl-aryl.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of formula I.
  • different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H or D).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the EXAMPLES herein using appropriate isotopically-enriched reagents and/or intermediates.
  • any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
  • a heteroaromatic ring described as containing from “1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range.
  • a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms.
  • C 1-6 when used with a chain means that the chain can contain 1, 2, 3, 4, 5 or 6 carbon atoms. It also includes all ranges contained therein including C 1-5 , CM, C 1-3 , C 1-2 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , and all other possible combinations.
  • a “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).
  • the compounds of the present invention are limited to stable compounds embraced by Formula I.
  • compound refers to the free compound and, to the extent they are stable, any hydrate or solvate thereof.
  • a hydrate is the compound complexed with water
  • a solvate is the compound complexed with an organic solvent.
  • the compounds of the present invention can be employed in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof).
  • a pharmaceutically acceptable salt can be formed, for example, by treating the compound of the invention (e.g., a compound of Formula I) with one molar equivalent of a mild base (e.g., sodium carbonate, sodium bicarbonate, potassium bicarbonate, or sodium acetate).
  • a mild base e.g., sodium carbonate, sodium bicarbonate, potassium bicarbonate, or sodium acetate
  • M is a cation, such as Na + in the event of treatment with a sodium base.
  • prodrugs of a compound of the invention which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of a compound of the invention that are readily convertible in vivo into compound of formula (I).
  • the present invention includes pharmaceutical compositions comprising a compound of Formula I of the present invention, optionally one or more other active components, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier will depend on the route of administration.
  • pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other, do not interfere with the effectiveness of the active ingredient(s), and are not deleterious (e.g., toxic) to the recipient thereof.
  • compositions according to the invention may, in addition to the inhibitor, contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • the present invention includes a method for treating a bacterial infection which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • subject or, alternatively, “patient” as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • administration and variants thereof (e.g., “administering” a compound) in reference to a compound of Formula I mean providing the compound, or a pharmaceutically acceptable salt thereof, to the individual in need of treatment.
  • “administration” and its variants are each understood to include provision of the compound or its salt and the other agents at the same time or at different times.
  • the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately.
  • a “combination” of active agents can be a single composition containing all of the active agents or multiple compositions each containing one or more of the active agents.
  • a combination can be either a single composition comprising both agents or two separate compositions each comprising one of the agents; in the case of three active agents a combination can be either a single composition comprising all three agents, three separate compositions each comprising one of the agents, or two compositions one of which comprises two of the agents and the other comprises the third agent; and so forth.
  • compositions and combinations of the present invention are suitably administered in effective amounts.
  • effective amount as used herein with respect to a nargenicin compound means the amount of active compound sufficient to inhibit DnaE and/or cause a bacteriocidal or bacteriostatic effect.
  • the effective amount is a “therapeutically effective amount” meaning the amount of active compound that can overcome bacterial drug resistance and which is sufficient to inhibit bacterial replication and/or result in bacterial killing.
  • compositions of the present invention are suitably parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, intraocular, or intrarectal, wherein the composition is suitably formulated for administration by the selected route using formulation methods well known in the art, including, for example, the methods for preparing and administering formulations described in chapters 39, 41, 42, 44 and 45 in Remington—The Science and Practice of Pharmacy, 21 st edition, 2006.
  • compounds of the invention are administered intravenously in a hospital setting.
  • administration is oral in the form of a tablet or capsule or the like.
  • the dosage of the compounds of the invention and of their pharmaceutically acceptable salts may vary within wide limits and should naturally be adjusted, in each particular case, to the individual conditions and to the pathogenic agent to be controlled.
  • the daily dose may be between 0.005 mg/kg to 100 mg/kg, 0.01 mg/kg to 10 mg/kg, 0.05 mg/kg to 5 mg/kg, 0.05 mg/kg to 1 mg/kg.
  • the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compound in the invention is provided in a pharmaceutical formulation for oral, intravenous, intramuscular, nasal, or topical administration.
  • the formulation can be prepared in a dosages form, such as but not limited to, a tablet, capsule, liquid (solution or suspension), suppository, ointment, cream, or aerosol.
  • the presently disclosed subject matter provides such compounds and/or formulations that have been lyophilized and that can be reconstituted to form pharmaceutically acceptable formulations for administration, for example, as by intravenous or intramuscular injection.
  • Intravenous administration of a compound of the invention can be conducted by reconstituting a powdered form of the compound with an acceptable solvent.
  • suitable solvents include, for example, saline solutions (e.g., 0.9% Sodium Chloride Injection) and sterile water (e.g., Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol).
  • the powdered form of the compound can be obtained by gamma-irradiation of the compound or by lyophilization of a solution of the compound, after which the powder can be stored (e.g., in a sealed vial) at or below room temperature until it is reconstituted.
  • the concentration of the compound in the reconstituted IV solution can be, for example, in a range of from about 0.1 mg/mL to about 20 mg/mL.
  • the methods of the presently disclosed subject matter are useful for treating these conditions in that they inhibit the onset, growth, or spread of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of a subject afflicted with, or at risk of, contracting the condition.
  • the terms “treat”, “treating”, and grammatical variations thereof, as well as the phrase “method of treating”, are meant to encompass any desired therapeutic intervention, including but not limited to a method for treating an existing infection in a subject, and a method for the prophylaxis (i.e., preventing) of infection, such as in a subject that has been exposed to a microbe as disclosed herein or that has an expectation of being exposed to a microbe as disclosed herein.
  • Infections that may be treatable by the compounds of the invention can be caused by a variety of microbes, including fungi, algae, protozoa, bacteria, and viruses.
  • the infection is a bacterial infection.
  • Exemplary microbial infections that may be treated by the methods of the invention include, but are not limited to, infections caused by one or more of Staphylococcus aureaus. Enterococcus faecalis.
  • Streptococcus species e.g., Streptococcus pyogenes and Streptococcus pneumoniae
  • Escherichia coli e.g., Streptococcus pyogenes and Streptococcus pneumoniae
  • Escherichia coli e.g., Streptococcus pyogenes and Streptococcus pneumoniae
  • Escherichia coli eudomonas aeruginosa
  • Burkholderia cepacia e.g., Proteus mirabilis and Proteus vulgaris
  • Klebsiella pneumoniae e.g., Acinetobacter baumannii
  • Strenotrophomonas maltophillia e.g., Streptococcus pyogenes and Streptococcus pneumoniae
  • the infection is an infection of a bacterium selected from Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.
  • a bacterium selected from Pseudomonas spp., Klebsiella spp., Enterobacter spp., Escherichia spp., Morganella spp., Citrobacter spp., Serratia spp. or Acintetobacter spp.
  • the compound of Formula (I), (Ia) or (Ib) is administered prophylactically to prevent or reduce the incidence of one of: (a) a bacterial infection in a subject at risk of infection; (b) a recurrence of a bacterial infection; and (c) combinations thereof. In some embodiments, the compound of Formula (I), (Ia) or (Ib), is administered to treat an existing bacterial infection.
  • the compound of Formula ((I), (Ia) or (Ib), is administered to treat an infection of a multi-drug resistant strain of bacterial (i.e., a strain that is resistant to two or more previously known anti-bacterial drugs, such as i) Carbapenemase producing Enterobacteriaceae that are resistant to Cephalosporins and certain carbapenems; ii) Extended spectrum ⁇ -lactamase (ESBL) producing Enterobacteriaceae that are resistant to cephalosporins and penicillins; iii) Aminoglycoside and Fluoroquinolone resistant Enterobacteriaceae; iv) Extended spectrum ⁇ -lactamase (ESBL) producing P.
  • a multi-drug resistant strain of bacterial i.e., a strain that is resistant to two or more previously known anti-bacterial drugs, such as i) Carbapenemase producing Enterobacteriaceae that are resistant to Cephalosporins and certain carbapenem
  • the compound of Formula (I), (Ia) or (Ib), has a minimum inhibitory concentration (MIC) against one or bacterial species of 25 ⁇ g/mL or less.
  • the compound of Formula (I), (Ia) or (Ib), is administered to treat an infection of a multi-drug resistant strain.
  • the compound of Formula I, Ia has a minimum inhibitory concentration (MIC) against one or more bacterial species of 25 ⁇ g/mL or less.
  • MICs can be determined via methods known in the art, for example, as described in Hurdle et al., 2008 , J. Antimicrob. Chemother. 62:1037-1045.
  • the methods of the invention further comprise administering to the subject an additional therapeutic compound.
  • the compound of the invention is administered to the subject before, after, or at the same time as one or more additional therapeutic compounds.
  • the additional therapeutic compound is an antibiotic.
  • the invention thus provides in a further aspect, a combination comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with one or more additional therapeutic agents.
  • additional therapeutic agents include, but not limited to, ⁇ -lactams, aminoglycosides, tetracyclines, macrocycles, oxazolidinones, glycopeptides, lipopeptides, quinolones, etc.,
  • the other antibiotic which may be combined with the compounds of formula I or Ia or Ib are, for example, Vancomycin, Linezolid, Tedizolid, Ceftaroline, Ceftobiprole, Ceftalozane, Daptomycin, Dalbavancin, Telavancin, Oritavancin, Aztreonam, Delafloxacin, GSK2140944, Plazomicin, Tigecycline, Solithromycin etc.,
  • Step 1 The Compound of formula (1) was prepared according to known methods available in the literature. The reaction was carried out in the presence of base, alkaline carbonates such as sodium carbonate, potassium carbonate and the like in a suitable solvent such as tetrahydrofuran (THF), dimethoxyethane, ether, dichloromethane (DCM), dimethylformamide (DMF), acetone and the like.
  • Step 2 The silyl group in compound of formula (1) was deprotected by mineral acids such as HCl, H 2 SO 4 and the like in presence of solvent such as tetrahydrofuran, dioxane, acetonitrile (ACN), dimethylformamide and the like to yield the compound of formula (2).
  • Step 3 The compound of formula (3) was obtained by reacting a compound of formula (2) with triphenylphosphine (PPh 3 ), formic acid and Diisopropyl azodicarboxylate (DIAD) in the presence of THF.
  • Step 4 The compound of formula (3) was hydrolyzed according to the procedure given in Bull Chem Soc Japan, 1976, 49, 510 to yield the compound of formula (4).
  • Step 5 The compound of formula (4) was reacted with triphenylphosphine, hydrazoic acid and DIAD according to the procedure given in Tetrahedron Letters, 1983, 49, 554, to yield the compound of formula (5).
  • Step 6 Reducing the Compound of formula (5) using reducing reagents such as triphenylphosphine, trimethylphosphine, triethylphosphine, tributylphosphine, methyl diphenylphosphinite or ethyldiphenylphosphinite and the like in presence of aqueous organic solvents such as tetrahydrofuran (THF), dioxane, acetonitrile (ACN), acetone, or dimethylformamide (DMF) containing about 1% to 50% water, preferably about 5% to 10% water and the like according to known Staudinger reaction gave the compound of formula (6).
  • reducing reagents such as triphenylphosphine, trimethylphosphine, triethylphosphine, tributylphosphine, methyl diphenylphosphinite or ethyldiphenylphosphinite and the like in presence of aqueous organic solvent
  • Step 7 The compound of formula (7) was synthesized by reacting a compound of formula (6) with amino protecting group in presence of organic base such as sodium bicarbonate and the like and water soluble solvents such as THF, dioxane and acetone followed by hydrolyzing using base such as LiOH and the like.
  • organic base such as sodium bicarbonate and the like and water soluble solvents such as THF, dioxane and acetone
  • base such as LiOH and the like.
  • Suitable amino-protecting groups include, for example, acyl groups such as formyl, acetyl and substituted acetyl (e.g., halogenated acetyl), benzoyl and substituted benzoyl, alkoxycarbonyl, halogenated alkoxycarbonyl, alkenyloxycarbonyl, aralkoxycarbonyl, halogenated aralkoxycarbonyl, benzyl and benzyl derivatives, trityl and trityl derivatives, sulfenyl derivatives, sulfonyl derivatives, diacyl derivatives such as phthalimido or succinimido or derivatives thereof and Schiff bases formed with aldehydes or ketones.
  • acyl groups such as formyl, acetyl and substituted acetyl (e.g., halogenated acetyl), benzoyl and substituted benzoyl, alkoxycarbonyl,
  • Step 8 The Compound of formula (7) was reacted with carbodiimidazole and magnesium mono p-nitrobenzyl malonate ester by a known method given in D. G. Melillo et al., Tetrahedron Letters, 1980, 21, 2783 to yield the compound of formula (8).
  • Step 9 The compound of formula (8) was subjected to a diazo-transfer reaction to yield compound of formula (9).
  • the compound of formula (8) was treated with an azide such as dodecabenzenesulfonylazide, 4-carboxybenzenesulfonylazide, p-toluenesulfonylazide, methanesulfonylazide and the like in presence of a base such as triethylamine (TEA), diethylamine, pyridine or lutidine and the like and solvent such as acetonitrile, dichloromethane, toluene, benzene and the like to yield the Compound of formula (9).
  • Step 10 The compound of formula (10) was synthesized by treating the compound of formula (9) with acids such as trifluoroacetic acid (TFA) or HCl and the like in presence of solvents such as dioxane or ether and the like.
  • Step 11a Reacting compound of formula (10) with R A COOH in the presence of coupling agents such as carbodiimides, phosphonium, uronium, guanidinium salts and the like and solvents such as ethyl acetate (EtOAc) and the like gave the compound of formula (11).
  • coupling agents such as carbodiimides, phosphonium, uronium, guanidinium salts and the like and solvents such as ethyl acetate (EtOAc) and the like gave the compound of formula (11).
  • Step 11b Reacting compound of formula (10) with R A X (X is Cl, Br, F, I) in the presence of acid binding agents such as alkali acetate, alkali hydroxide, calcium oxide, calcium carbonate, magnesium carbonate or organic bases such as pyridine, N-methyl morpholine, diisopropylethylamine (DIPEA), TEA and the like and solvents such as DCM, dioxane, toluene and the like gave the compound of formula (11).
  • acid binding agents such as alkali acetate, alkali hydroxide, calcium oxide, calcium carbonate, magnesium carbonate or organic bases such as pyridine, N-methyl morpholine, diisopropylethylamine (DIPEA), TEA and the like
  • DIPEA diisopropylethylamine
  • solvents such as DCM, dioxane, toluene and the like gave the compound of formula (11).
  • Step 11c The compound of formula (10) was reacted with carbonylating agent such as phosgene, diphosgene, triphosgene, N,N′-carbonyldiimidazole (CDI), thiophosgene, thiocarbonyldiimidazole and the like in presence of bases such as pyridine, N-methyl morpholine, DIPEA, TEA and the like in solvents such as DCM, 1,2-dichloromethane, toluene, ACN and the like and successively treated with R A OH/R A NH 2 to yield the compound of formula (11).
  • carbonylating agent such as phosgene, diphosgene, triphosgene, N,N′-carbonyldiimidazole (CDI), thiophosgene, thiocarbonyldiimidazole and the like
  • bases such as pyridine, N-methyl morpholine, DIPEA, TEA and the like
  • solvents
  • Step 11d The compound of formula (a) was reacted with R 3 OH in presence of triphenylphosphine and DIAD in solvents such as THF and the like to obtain a compound of formula (11).
  • Step 11e The compound of formula (b) was reacted with compound (c) in presence of copper iodide and DIPEA in solvents such as toluene and the like to obtain a compound of formula (11).
  • Step 12 The compound of formula (12) was prepared by reacting a compound of formula (11) with the compound of general formula H—SR 1 , wherein the R 1 is as defined earlier in presence of activating agent such as diphenyl chlorophosphate, dimethylaminopyridine (DMAP) and the like and catalyst such as bis(acetylacetonate)Cu(II), copper sulfate, copper powder, rhodium acetate [Rh 2 (OAc) 4 ], rhodium(II)octanoate, Pd(OAc) 2 , Pb(OAc) 4 and the like and solvents such as tetrahydrofuran, ethyl acetate, benzene, toluene, hexane, cyclohexane and the like.
  • activating agent such as diphenyl chlorophosphate, dimethylaminopyridine (DMAP) and the like
  • catalyst such as bis(acetylacetonate)Cu(I
  • Step 12a Reacting the compound of formula (12) with 2-iodoacetamide or iodomethane and the like in presence of solvents such as THF-acetone and the like gave the compound of formula (I), (Ia) or (Ib).
  • Step 13 The compound of formula (I), (Ia) or (Ib), was prepared by reducing the compound of formula (12) or the compound of formula (12a) with Pd/C in presence of solvents such as THF-water and the like under pressure.
  • Step 14 Hydroxymethylation by a cross coupling reaction between carbapenem-2-triflate and Bu 3 SnCH 2 OH.
  • Step 15 Allylic carbonate (14) was prepared by isobutylchloroformate in presence of DIPEA, DMAP and in solvents like dichloromethane and tetrahydrofuran.
  • Step 16 Allylic amine (15) was prepared by reaction of allylic carbonate (14) and amine in presence of Palladium catalyst.
  • Step 17 Formula (Ia) was prepared by reducing the compound of formula (15) with Pt/C in presence of solvents such as THF-water and the like under pressure.
  • Aqueous hydrochloric acid (2 N, 10 mL) was added to 10 g of (R)-benzyl-2-((2S′,3S)-3-((R)-1-(t-butyldimethylsilyloxy)ethyl)-4-oxoazetidin-2-yl)propanoate (10 g) dissolved in acetonitrile (100 mL) and stirred at room temperature for 3 hours. Reaction mixture was concentrated to obtain crude oil, which was dissolved in ethyl acetate (250 mL). The organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated under vacuum.
  • reaction mixture was further stirred at ice-cold condition for a period of 30 minutes. Subsequently, water (50 mL) was added and the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated under vacuum. The residue thus obtained was stirred with toluene (100 mL) and filtered. The filtrate was concentrated to yield oily crude. The crude thus obtained was purified by column chromatography to yield the product as an oily substance (3.32 g, 30.2%).
  • Triphenylphosphine (6.51 g, 24.8 mmoles) was added to a solution of (R)-benzyl 2-((2S. 3S)-3-((R)-1-azidoethyl)-4-oxoazetidin-2-yl)propanoate (5 g, 16.6 mmoles) in tetrahydrofuran (25 mL) and the mixture was stirred at room temperature for 5 hours under nitrogen atmosphere. To the reaction mixture, water (5 mL) was added and it was stirred at room temperature for a period of 16 hours. Brine solution (50 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL).
  • Lithium hydroxide (0.768 g, 32.07 mmoles) was added to the solution of (R)-benzyl 2-((2S,3R)-3-((R)-1-(t-butoxycarbonylamino)ethyl)-4-oxoazetidin-2-yl)propanoate (10 g, 26.56 mmoles) in 50 mL of tetrahydrofuran:methanol:water (1:1:0.5) at ice-cold condition. The reaction mixture was continued to be stirred at room temperature for 1 hour. The reaction mixture was concentrated and diluted with water (150 mL). The aqueous layer was washed with EtOAc (150 mL).
  • Trifluoroacetic acid (1.40 g, 12.3 mmoles) was added to a solution of (R)-4-nitrobenzyl 4-((2R,3R)-3-((R)-1-(t-butoxycarbonylamino)ethyl)-4-oxoazetidin-2-yl)-2-diazo-3-oxopentanoate (2 g, 4.08 mmoles) in dichloromethane (10 mL) at ice-cold condition and stirred for 2 hours at nitrogen atmosphere. The reaction mixture was concentrated and the residue obtained was triturated with diethyl ether to yield the product as a white solid.
  • reaction mixture was stirred for 5 hours at room temperature. On completion of reaction (as measured by TLC), the reaction mixture was diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and the solvent was evaporated to obtain the crude as an oily substance.
  • the crude product was treated with toluene (10 mL) and stirred at 0° C. for 30 minutes, filtered and washed with 10 mL of toluene (cold). The filtrate and the washings were mixed together and concentrated to obtain crude product.
  • the crude product on purification by column chromatography (15% EtOAc in hexane) yields the title product (0.9 g, 34.6%).
  • O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 70.8 g, 0.22 mol) was added to a mixture of pivalic acid (15 g, 0.147 mol) and triethylamine (35 mL, 0.25 mol) in ethyl acetate (150 mL) and stirred for 0.5 hour at room temperature.
  • Glycine ethyl ester HCl (20.52 g, 0.147 mol) was added to the above at 0° C. and the reaction mixture was stirred for 16 hours at room temperature.
  • Step 1 (4R,5S,6S)-4-Nitrobenzyl 3-((3S,5S)-5-(dimethylcarbamoyl)-1-((4-nitrobenzyloxy)carbonyl)pyrrolidin-3-ylthio)-4-methyl-6-((R)-1-(methylsullonamido) ethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
  • Diisopropylethylamine (0.25 mL, 1.43 mmoles), catalytical amount of dimethylaminopyridine and diphenylchlorophosphate (0.26 mL, 1.28 mmoles) were added successively to the reaction mixture and stirred for 30 minutes at ⁇ 50 to ⁇ 40° C.
  • (2S,4S)-4-nitrobenzyl-2-(dimethylcarbamoyl)-4-mercaptopyrrolidine-1-carboxylate (0.374 g, 1.06 mmoles) and diisopropylethylamine (0.25 mL, 1.43 mmoles) were added to the reaction mixture and continued stirring at ⁇ 20° C. for 1 hour.
  • reaction mixture was then warmed to 0° C. and the stirring was continued for a further period of 3 hours.
  • the reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (50 mL). The separated organic layer was washed with water and brine. After drying over sodium sulphate, the organic layer was concentrated to obtain the crude, which on purification by column chromatography, yielded a white solid 0.4 g-48% (compound eluted with 20-30% acetone in dichloromethane).
  • Step 2 (4R,5S,6S)-3-((3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-ylthio)-4-methyl-6-((R)-1-(methylsulfonamido)ethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  • Examples 2-6, 17, 21, 26, 28, 31, 32, 35, 37-38, 40, 42-46, 49-50, 53-56, 58-68, 70-85 and 87-94 were prepared by treating the compound of formula (10) with appropriate R A COOH according to the procedure given in the preparations 12, 16 and 17, followed by the procedure given in Example 1.
  • Examples 7-16, 18-19, 23-25, 27, 29-30, 33-34, 39, 48, 51, 57 and 86 were prepared by treating the compound of formula (10) with appropriate R A X according to the procedure given in preparation 13 and 14, followed by the procedure given in Example 1.
  • Examples 20, 22, 36, 41, 47, 52 and 69 were prepared by treating the compound of formula (10) with appropriate carbonylating agents according to the procedure given in the preparation 15 followed by the procedure given in example 1.
  • the quaternization of the heterocyclic rings in Examples 39, 45, 46, 80 and 94 were carried out according to the procedure given in preparation 19.
  • Step-1 (4R,5R,6R)-4-nitrobenzyl 3-(diphenoxyphosphoryloxy)-4-methyl-6-((R)-1-(2-(methyl((4-nitrobenzyloxy)carbonyl)amino)acetamido)ethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
  • Rhodium octanoate (0.1 g, 0.128 mmoles) was added to a solution of (R)-4-nitrobenzyl 2-diazo-4-((2R,3R)-3-((R)-1-(2-(methyl((4-nitrobenzyloxy)carbonyl)amino) acetamido) ethyl)-4-oxoazetidin-2-yl)-3-oxopentanoate (3 g, 4.69 mmoles) in acetone (60 mL) and heated to reflux for 1.5 hours. The reaction mixture was cooled to ⁇ 50 to ⁇ 40° C.
  • Step-2 (4R,5S,6R)-4-nitrobenzyl4-methyl-6-((R)-1-(2-(methyl((4-nitrobenzyloxy) carbonyl)amino)acetamido)ethyl)-3-((3S,5S)-1-((4-nitrobenzyloxy)carbonyl)-5-((R)-3-((4-nitrobenzyloxy)carbonylamino)pyrrolidine-1-carbonyl)pyrrolidin-3-ylthio)-7-oxo-1-azabicycio[3.2.0]hept-2-ene-2-carboxylate
  • Step-3 (4R,5S,6R)-3-((3R,5S)-5-((R)-3-aminopyrrolidine-1-carbonyl)pyrrolidin-3-ylthio)-4-methyl-6-((R)-1-(2-(methylamino)acetamido)ethyl)-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylic acid
  • reaction mixture was filtered over celite and washed with 30 mL of tetrahydrofuran: water (2:1) mixture. The filtrate was washed with EtOAc (30 mL ⁇ 6). The aqueous layer was treated with charcoal (1 g) and filtered. The filtrate was lyophilized to yield the title compound (0.1 g, 50%).
  • Examples 96, 97, 100-135, 137-145, 147-166, 168-176, 178-186, 188-200, 202, 205-206, 209-231, 235-238, 241-273, 275-292, 294-297, 299-312, 314-318, 320-325, 329-361 and 363-368 were prepared by treating the compound of formula (10) with appropriate R A COOH according to the procedure given in the preparations 12, 16 and 17, followed by the procedure given in Example 1.
  • Examples 136, 201, 203, 204, 239, 240 and 362 were prepared by following the procedure provided in preparation 13.
  • Example 187 was prepared by following the procedure provided in preparation 19.
  • Example 98 and 99 were prepared by following the procedure given in preparation 23.
  • Examples 146, 167, 177, 207, 208, 232-234 were prepared by following the procedure described in the preparation 20 using appropriate alkynes (cf. Scheme 2a).
  • Example 274 and 293 were prepared by following the procedure provided in preparation 24.
  • Example 298 (4R,5S,6R)-6-((R)-1-(2-(1H-tetrazol-1-yl) acetamido)ethyl)-3-((3S,5S)-5-((R)-3-aminopyrrolidine-1-carbonyl)pyrrolidin-3-ylthio)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  • Step 1 (R)-4-Nitrobenzyl 4-((2R,3R)-3-((R)-1-(2-(1H-tetrazol-1-yl)acetamido)ethyl)-4-oxoazetidin-2-yl)-2-diazo-3-oxopentanoate
  • Trifluoroacetate salt of (R)-4-nitrobenzyl 4-((2R,3R)-3-((R)-1-aminoethyl)-4-oxoazetidin-2-yl)-2-diazo-3-oxopentanoate (17.5 g, 44 mmol) was diluted with ethyl acetate (75 mL) and was neutralized using diisopropylethylamine (5 mL) at 0° C. This solution was then added to the aforementioned reaction mixture at 0° C. under N 2 atmosphere. After the addition was complete the reaction mixture was brought to room temperature and stirred for 14 hours under N 2 atmosphere.
  • Step 2 (4R,5R,6R)-4-Nitrobenzyl 6-((R)-1-(2-(1H-tetrazol-1-yl)acetamido)ethyl)-3-(diphenoxyphosphoryloxy)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
  • Step 3 (4R,5S,6R)-4-nitrobenzyl 6-((R)-1-(2-(1H-tetrazol-1-yl)acetamido)ethyl)-4-methyl-3-((3S,5S)-1-((4-nitrobenzyloxy)carbonyl)-5-((R)-3-((4-nitrobenzyloxy)carbonylamino)pyrrolidine-1-carbonyl)pyrrolidin-3-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
  • Step 4 (4R,5S,6R)-6-((R)-1-(2-(1H-tetrazol-1-yl)acetamido)ethyl)-3-((3S,5S)-5-((R)-3-aminopyrrolidine-1-carbonyl)pyrrolidin-3-ylthio)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  • reaction was kept for 1.5 hours at 5 Kg hydrogen pressure.
  • the reaction mixture was then filtered through filter paper and was washed with ethyl acetate (5 ⁇ 50 mL).
  • the reaction mixture was treated with charcoal and filtered.
  • the aqeuous layer was again given ethyl acetate washing and was kept under lyophilization for 2 days to give the final product as a white solid (400 mg, 51.34%).
  • Step 4B (4R,5S,6S)-6-((R)-1-(2H-tetrazol-2-yl)ethyl)-3-((3S,5S)-5-(dimethylcarbamoyl)-pyrrolidin-3-ylthio)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  • Step 1 (R)-4-nitrobenzyl 4-((2R,3S)-3-((R)-1-(1H-tetrazol-1-yl)ethyl)-4-oxoazetidin-2-yl)-2-diazo-3-oxopentanoate (A) and (R)-4-nitrobenzyl 4-((2R,3S)-3-((R)-1-(2H-tetrazol-2-yl)ethyl)-4-oxoazetidin-2-yl)-2-diazo-3-oxopentanoate (B)
  • Step 2A (4R,5R,6S)-4-nitrobenzyl 6-((R)-1-(1H-tetrazol-1-yl)ethyl)-3-(diphenoxyphosphoryloxy)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
  • Step 3A (4R,5S,6S)-4-nitrobenzyl 6-((R)-1-(1H-tetrazol-1-yl)ethyl)-3-((3S,5S)-5-(dimethylcarbamoyl)-1-((4-nitrobenzyloxy)carbonyl)pyrrolidin-3-ylthio)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
  • the product obtained (0.25 g, 0.39 mmol) from step 2A was taken in 10 mL of acetonitrile and cooled to 0° C. and degassed for 10 minutes.
  • To this reaction mixture was added the thiol (0.22 g, 0.39 mmol) followed by diisopropylethylamine (0.1 mL, 0.57 mmol) under N 2 atmosphere.
  • the reaction mixture was again degassed for 10-15 minutes. Further the reaction mixture was stirred at 0° C. for 2 hours.
  • the reaction mixture was added with water and extracted using ethyl acetate. The organic layer was concentrated and the resultant crude mixture was purified by column chromatography to give the product (260 mg, 33.6%).
  • Step 4A (4R,5S,6S)-6-((R)-1-(1H-tetrazol-1-yl)ethyl)-3-((3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-ylthio)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  • Examples 326-328 were prepared by following the procedure described in preparations 313 & 319 using appropriately substituted tetrazoles.
  • Example 328 was prepared by reacting compound obtained by Step 2A with appropriate R 1 —SH group followed by the procedure of steps 3A and 4A or Example 319.
  • Examples 334 and 335 were prepared by reacting compound obtained by Step 2 with appropriate R1-SH group followed by the procedure in step 3 of Example 347.
  • Example 347 ((4R,5S,6R)-3-((3S,5S)-5-((R)-3-aminopyrrolidine-1-carbonyl)pyrrolidin-3-ylthio)-4-methyl-7-oxo-6-((R)-1-(2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetamido)ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid)
  • Ethyl 2-(2,2,2-trifluoroethanethioamido)acetate (11 g, 0.051 mol) was dissolved in dichloromethane (110 mL) at ambient temperature.
  • Azidotrimethylsilane (13.5 ml, 0.102 mol) was added dropwise to this solution and stirred for 10 minutes.
  • a solution of SnCl 4 (13.3 mL, 0.127 mmol) in dichloromethane (mL) was added dropwise and stirred for 15 minutes. The reaction mixture was then stirred overnight at room temperature.
  • the reaction mixture was then quenched with saturated NaHCO 3 solution slowly at 0° C., filtered through celite bed, washed with dichloromethane.
  • Step 1 (R)-4-Nitrobenzyl2-diazo-3-oxo-4-((2R,3R)-4-oxo-3-((R)-1-(2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetamido)ethyl)azetidin-2-yl)pentanoate
  • Step 2 (4R,5R,6R)-4-nitrobenzyl 3-(diphenoxyphosphoryloxy)-4-methyl-7-oxo-6-((R)-1-(2-(5-(trifluoromethyl)-1H-tetrazol-1-yl)acetamido)ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
  • Step 3 (4R,5S,6R)-4-Nitrobenzyl 4-methyl-3-((3S,5S)-1-((4-nitrobenzyloxy) carbonyl)-5-((R)-3-((4-nitrobenzyloxy)carbonylamino)pyrrolidine-1-carbonyl) pyrrolidin-3-ylthio)-7-oxo-6-((R)-1-(2-(5-(trifluoromethyl)-1H-tetrazol-1-yl) acetamido)ethyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
  • Example 348 was prepared by reacting compound obtained by Step 2 with appropriate R 1 —SH group followed by the procedure of step 3 of Example 347.
  • Examples 369-378 and 383-451 were prepared by treating the compound of formula (10) with appropriate R A COOH according to the procedure given in the preparations 12, 16 and 17, followed by the procedure given in Example 1.
  • reaction mixture was diluted with ethyl acetate and 0.1M phosphate buffer 7.0. Organic layer was separated and washed with water and brine. After drying over sodium sulphate, organic layer was concentrated to obtain crude. The crude was purified by column chromatography to obtain the titled compound (0.06 g).
  • Example 601 Synthesis of (5R,6R)-6-((R)-1-(2-(1H-tetrazol-1-yl)acetamido)ethyl)-3-((3S,5S)-5-(octahydro-1H-pyrrolo[3,2-c]pyridine-1-carbonyl)pyrrolidin-3-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  • the reaction was diluted with water (1 L).
  • the aqueous layer was washed with ethyl acetate (500 mL ⁇ 2).
  • the aqueous layer was cooled to 0° C. and the pH was adjusted with 6 N HCl to 8.
  • the aqueous layer was washed with ethyl acetate (500 mL ⁇ 2).
  • the aqueous layer was acidifed to pH 3 with dil HCl and extracted with ethyl acetate (400 mL ⁇ 2).
  • strains include methicillin-sensitive Staphylococcus aureus , carbapenem sensitive Escherichia coli , extended spectrum ⁇ lactamase (ESBL) SHV18 producing Klebsiella pneumoniae , carbapenemase producing K. pneumoniae, Enterobacter spp; Morganello spp; citrobacter spp; serratia spp; acinetobacter and carbapenem sensitive Pseudomonas aeruginosa.
  • ESBL extended spectrum ⁇ lactamase
  • Antibacterial activity was evaluated by determining the minimum inhibitory concentration (MIC) of these compounds by broth micro-dilution method (CLSI guidelines, M7-A7/Jan 2006, M100-S18/Jan 2008). Two-fold serial dilutions of the test compounds in Mueller-Hinton broth were prepared in 96 well micro-titre plates. To these dilutions, equal amount of Mueller-Hinton broth containing bacterial suspensions were added to obtain a 5 ⁇ 10 5 colony forming units per mL. MIC of the test compounds was determined after incubating micro-titre plates at 35° C. for 22 hours. The minimum concentration of the compound that inhibited visible growth of bacteria is defined as MIC.

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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4194047A (en) 1975-11-21 1980-03-18 Merck & Co., Inc. Substituted N-methylene derivatives of thienamycin
EP0017992A1 (en) 1979-04-19 1980-10-29 Merck & Co. Inc. 2-Substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids, processes for preparing them, antibiotic pharmaceutical compositions containing same and process for preparing intermediates
EP0059554A2 (en) 1981-02-27 1982-09-08 Beecham Group Plc Beta-lactam antibiotics, a process for their preparation and their use in pharmaceutical compositions
JPS57158785A (en) 1981-02-27 1982-09-30 Beecham Group Ltd Beta-lactam antibiotic, manufacture and medicinal composition
US4413000A (en) 1980-07-11 1983-11-01 Beecham Group Limited β-Lactam antibiotics, their preparation and use
EP0372582A2 (en) 1988-12-09 1990-06-13 Bristol-Myers Squibb Company 6-Aminoalkyl carbapenems
EP0518558A1 (en) 1991-06-04 1992-12-16 Sankyo Company Limited 1-Methylcarbapenem derivatives, their preparation and their use as antibiotics
JPH0748375A (ja) 1994-05-09 1995-02-21 Sankyo Co Ltd １−メチルカルバペネム誘導体
EP0126587B1 (en) 1983-05-09 1995-04-19 Sumitomo Pharmaceuticals Company, Limited Carboxylic thio-pyrrolidinyl beta-lactam compounds and production thereof
EP0579826B1 (en) 1992-02-04 1998-11-11 Zeneca Limited Carbapenems containing a carboxy substituted phenyl group, processes for their preparation, intermediates and use as antibiotics
RU2130457C1 (ru) 1993-03-16 1999-05-20 Американ Цианамид Компани 2-тиозамещенные карбапенемы, промежуточные соединения для получения, способы получения (варианты), фармацевтическая композиция
EP0528678B1 (en) 1991-08-20 2001-05-23 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. A pyrrolidylthiocarbapenem derivative with antibacterial activity

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60233076A (ja) * 1984-05-03 1985-11-19 Sumitomo Chem Co Ltd 新規なβ−ラクタム化合物およびその製造法
JPS6383062A (ja) * 1986-09-26 1988-04-13 Nippon Redarii Kk アゼチジンスルホン酸誘導体
JPH04211083A (ja) * 1990-02-23 1992-08-03 Sankyo Co Ltd カルバペネム−３−カルボン酸誘導体
JP2934283B2 (ja) * 1990-05-29 1999-08-16 第一製薬株式会社 カルバペネム誘導体
JP3411589B2 (ja) * 1992-05-11 2003-06-03 第一製薬株式会社 カルバペネム誘導体

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4194047A (en) 1975-11-21 1980-03-18 Merck & Co., Inc. Substituted N-methylene derivatives of thienamycin
EP0017992A1 (en) 1979-04-19 1980-10-29 Merck & Co. Inc. 2-Substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids, processes for preparing them, antibiotic pharmaceutical compositions containing same and process for preparing intermediates
JPS565478A (en) 1979-04-19 1981-01-20 Merck & Co Inc 22substitutedd66substituteddcarbadethiapenee 22emm33carboxylic acid
US4413000A (en) 1980-07-11 1983-11-01 Beecham Group Limited β-Lactam antibiotics, their preparation and use
EP0059554A2 (en) 1981-02-27 1982-09-08 Beecham Group Plc Beta-lactam antibiotics, a process for their preparation and their use in pharmaceutical compositions
JPS57158785A (en) 1981-02-27 1982-09-30 Beecham Group Ltd Beta-lactam antibiotic, manufacture and medicinal composition
EP0126587B1 (en) 1983-05-09 1995-04-19 Sumitomo Pharmaceuticals Company, Limited Carboxylic thio-pyrrolidinyl beta-lactam compounds and production thereof
EP0372582A2 (en) 1988-12-09 1990-06-13 Bristol-Myers Squibb Company 6-Aminoalkyl carbapenems
EP0518558A1 (en) 1991-06-04 1992-12-16 Sankyo Company Limited 1-Methylcarbapenem derivatives, their preparation and their use as antibiotics
EP0528678B1 (en) 1991-08-20 2001-05-23 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. A pyrrolidylthiocarbapenem derivative with antibacterial activity
EP0579826B1 (en) 1992-02-04 1998-11-11 Zeneca Limited Carbapenems containing a carboxy substituted phenyl group, processes for their preparation, intermediates and use as antibiotics
RU2130457C1 (ru) 1993-03-16 1999-05-20 Американ Цианамид Компани 2-тиозамещенные карбапенемы, промежуточные соединения для получения, способы получения (варианты), фармацевтическая композиция
JPH0748375A (ja) 1994-05-09 1995-02-21 Sankyo Co Ltd １−メチルカルバペネム誘導体

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
Bassetti et al., "Current Status of Newer Carbapenems" Current Medicinal Chemistry, vol. 16, No. 5, (2009) (pp. 564-575).
Bassetti et al., Current Medicinal Chemistry, vol. 16, No. 5, Abstract (2009).
Chaudhary et al., Indian Journal of Medical Microbiology, 2004, 22(2), 75-80.
Corbett, David F. et al., "Chemical Modification of the Olivanic Acids: Synthesis of Substituted 6-[1-(1,2,3-Triazol-1-yl)Ethyl] Carbapenem Derivative", Tetrahedron Letters, 1983, vol. 24 (49), p. 5543-5546.
Falagas et al., Journal of Antimicrobial Chemotherapy, 2007, 60, 1124-1130.
International Search Report and Written Opinion EP ISA dated Aug. 9, 2017 (PCT/IN2017/000060).
RU Official Action dated Apr. 15, 2020 (English translation).
RU Search Report dated Apr. 15, 2020 (English translation).
Sumita, Y et al., Journal of Antibiotics, 1995, 48(2), 188-190.
Sunagawa M et al., Journal of Antibiotics, 1997, 50(7), 621-627.

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